Persons who have exceptionally high risk of developing cancer are studied to find explanations for their susceptibility. These unusual individuals are identified through referral by practitioners and by our own clinical observations at the bedside. With informed consent, epidemiologic inquiries are made to identify predisposing host and environmental factors, and to quantify the risk of cancer development. Concurrent laboratory studies are made to clarify biologic mechanisms of cancer susceptibility. Results show that carriers of cancer genes develop cancer at high rates in specific tissues, including multiple primary cancers in childhood. In the dominantly inherited syndrome of breast cancer, sarcomas and other early-onset neoplasms (Li-Fraumeni family cancer syndrome), the inherited cancer susceptibility was shown to be due to the p53 gene.